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Name d-Thioctic acid;(R)-(+)-alpha-Lipoic acid;(R)-(+)-Thioctic acid;Dexlipotam
Chemical Name (+)-5-[1,2-Dithiolan-3(R)-yl]pentanoic acid
CAS 1200-22-2
Related CAS
Formula C8H14O2S2
Structure
Formula Weight 206.32758
Stage II 期临床
Company Asta Medica (Originator), Aventis Pharma (Licensee)
Activity/Mechanism Antidiabetic Drugs, Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Treatment of Diabetic Complications, Type 2 Diabetes Mellitus, Agents for, Pyruvate Dehydrogenase Activators
Syn. Route 20
Route 1
aldehyde (ii), prepared by ozonolysis of cyclohexene (i), was ketalized with (s,s)-2,4-pentanediol (iii) to afford dioxane (iv). titanium chloride-mediated coupling of acetal (iv) with the ketene acetal (v) afforded diastereoselectively adduct (vi), which was subsequently hydrolyzed to carboxylic acid (vii) by means of trifluoroacetic acid. removal of the pentanediol moiety to furnish the (r)-alcohol (ix) was accomplished via jones oxidation of the secondary alcohol (vii) to ketone (viii), followed by beta-elimination in the presence of piperidinium acetate. reduction of the free carboxyl group by borane-tetrahydrofuran complex gave diol (x), which was further converted to dimesylate (xi). disulfide displacement of the mesylate groups provided (+)-lipoic acid isopropyl ester (xii), which was finally hydrolyzed to the title acid using k2co3 in meoh/h2o.
List of intermediates No.
n-[2-(diethylamino)ethyl]-n-{[4-(trifluoromethyl)[1,1-biphenyl]-4-yl]methyl}amine; n~1~,n~1~-diethyl-n~2~-{[4-(trifluoromethyl)[1,1-biphenyl]-4-yl]methyl}-1,2-ethanediamine (i)
Reference 1:
    elliott, j.d.; et al.; asymmetric synthesis via acetal templates. 12. highly diastereoselective coupling reactions with a ketene acetal. an efficient, asymmetric synthesis of r-(+)-alpha-lipoic acid. tetrahedron lett 1985, 26, 21, 2535.

Route 2
alkylation of the lithio-dianion of propargyl alcohol (xiii) with 6-bromo-1-hexene (xiv), followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (xv). asymmetric sharpless epoxidation of (xv) using tert-butyl hydroperoxide in the presence of l-(+)-diisopropyl tartrate afforded the (s,s)-epoxy alcohol (xvi). this was reduced to the chiral diol (xvii) employing red-al? in thf. after formation of the bis-mesylate (xviii), oxidative cleavage of the terminal double bond by means of naio4 in the presence of ruthenium catalyst furnished the carboxylic acid (xix). the mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.
List of intermediates No.
1-allyl-2-bromopyridinium bromide (xiii)
2-(3-bromobenzylidene)malononitrile (xiv)
Reference 1:
    page, p.c.b.; et al.; an enantioselective synthesis of r-(+)-alpha-lipoic acid. j chem soc - perkins trans i 1990, 6, 1615.
Reference 2:
    bulman, p.c.; et al.; enantioselective synthesis of r-(+)-alpha-lipoic acid. j chem soc chem commun 1986, 18, 1408.
Reference 3:
    sutherland, i.o.; page, p.c.b.; rayner, c.m. (asta medica ag); process for the preparation of pure enantiomers of r-(+)-alpha-lipoic acid and s-(-)-alpha-lipoic acid (thioctic acid), and nonene or mesyl derivs. as intermediates thereof. de 3629116; ep 0261336 .

Route 3
an alternative route to (+)-lipoic acid used ethyl 4,6-di-o-acetyl-2,3-dideoxy-alpha-d-erythro-hexopyranoside (xx), prepared from triacetyl-d-glucal, as the chiral starting point. deacetylation of (xx) with sodium methoxide under zemplen conditions gave diol (xxi) which, after conventional benzylation, led to the 4,6-di-o-benzyl derivative (xxii). ring opening of the cyclic acetal (xxii) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (xxiii). the free hydroxyl group of (xxiii) was converted into xanthate (xxiv) by reaction with nah and cs2, followed by methyl iodide. reductive cleavage of the xanthate group by means of bu3snh and aibn provided (xxv). hydrolysis of the thioacetal function with hgo and bf3 provided aldehyde (xxvi). chain homologation was performed by wittig reaction of aldehyde (xxvi) with phosphorane (xxvii) to afford the unsaturated ester (xxviii). simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of raney nickel led to dihydroxy ester (xxix). this was converted to the corresponding dimesylate (xxx), which was further cyclized to disulfide (xxxi) using the in situ generated sodium disulfide as in the precedent schemes. finally, basic hydrolysis of the ethyl ester (xxxi) yielded the title carboxylic acid.
List of intermediates No.
2-chloro-1-(3-pyridinyl)-1-ethanone (xxvii)
Reference 1:
    rao, a.v.r.; et al.; enantiospecific synthesis of (r)-(+)-alpha-lipoic acid from d-glucose. carbohydr res 1986, 148, 1, 51.

Route 4
a short synthetic strategy utilized the cyclic thioketal (xxxiii), derived from d-menthone (xxxii) and 1,3-propanedithiol, as the chiral template. stereospecific oxidation of dithiane (xxxiii) employing naio4 produced sulfoxide (xxxiv). the carbanion generated from sulfoxide (xxxiv) was stereoselectively alkylated by 5-bromopentanoic acid (xxxv) in the presence of tmeda to furnish the trans alkylated compound (xxxvi). finally, acidic hydrolysis of (xxxvi) formed the intermediate mercapto sulfinic acid (xxxvii) which spontaneously cyclized to the desired dithiolane derivative.
List of intermediates No.
(2s)-2-amino-1-(1h-indol-3-yl)-3,3-dimethyl-1-butanone (xxxii)
Reference 1:
    menon, r.b.; et al.; stereospecific synthesis of alpha-lipoic acid. tetrahedron lett 1987, 28, 44, 5313.

Route 5
a different strategy was based on the enantioselective oxidation of a cyclohexanone derivative by enzymic baeyer-villiger reaction. keto ester (xxxviii) was protected as the ethylene ketal (xxxix) and subsequently reduced to alcohol (xl) using lialh4. acetylation of alcohol (xl) to acetate (xli), followed by acidic ketal hydrolysis afforded cyclohexanone (xlii) (9,10). the racemic ketone (xlii) was then subjected to oxidative cleavage by monooxigenase 2 obtained from pseudomonas putida to furnish the (r)-lactone (xliv) along with unreacted (s)-cyclohexanone (xliii) (9-11). the use of cyclohexanone monooxigenase from acinetobacter ncimb 9871 has also been reported for this reaction (12). methanolysis of lactone (xliv) in the presence of naome gave rise to the (r)-dihydroxy ester (xlv). inversion of the configuration of (xlv) was accomplished by mitsunobu coupling with p-nitrobenzoic acid (xlvi) to produce the (s)-p-nitrobenzoate ester (xlvii). smooth hydrolysis of ester (xlvii) provided methyl (s)-6,8-dihydroxyoctanoate (xlviii), which was processed through intermediates (xlix) and (l), as for the isopropyl (x) (scheme 29605101a) and ethyl (xxix) (scheme 29605103a) homologues, to afford the title compound.
List of intermediates No.
11-[[11-(acetoxy)undecanoyl]peroxy]-11-oxoundecyl acetate (xlvi)
Reference 1:
    adger, b.; et al.; the synthesis of (r)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. bioorg med chem 1997, 5, 2, 253.
Reference 2:
    adger, b.; et al.; application of enzymatic baeyer-villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (r)-(+)-lipoic acid. j chem soc chem commun 1995, 15, 1563.
Reference 3:
    mccague, r.; roberts, s.m.; adger, b.m. (celltech group plc); process for the production of lipoic acid. wo 9638437 .

Route 6
a synthetic route based on the asymmetric reduction of oxo diesters has been reported. meldrums acid (lii) was acylated by methyl adipoyl chloride (li) in the presence of pyridine to produce the intermediate (liii) which, upon alcoholysis with isobutanol, led to oxo diester (liv). enantioselective reduction of (liv) by means of bakers yeast furnished the (s)-hydroxy diester (lv). alternatively, the analogous oxo diester (lvi) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (li), followed by deacetylation in the presence of ammonium hydroxide. then, asymmetric chemical reduction of (lvi) by hydrogenation in the presence of the chiral catalyst ru2cl4[(s)-binap]2 provided the (s)-hydroxy diester (lvii). regioselective reduction of either diester (lv) or (lvii) by means of nabh4 in refluxing thf furnished dihydroxy ester (xlviii). after conversion of (xlviii) to the dimesylate (xlix), displacement with potassium thioacetate afforded the bis(acetylthio) derivative (lviii), which was further hydrolyzed with koh to provide dihydrolipoic acid (lix). in a related procedure, dihydrolipoic acid (lix) was prepared by reaction of dimesylate (xlix) with sodium disulfide, followed by reductive treatment with nabh4 and naoh. the title cyclic disulfide was then obtained by oxidation of the dithiol (lix) using oxygen in the presence of fecl3.
List of intermediates No.
tert-butyl (5s)-5-amino-6-([(1s)-1-[([(1s)-2-[[(1s)-1-(aminocarbonyl)-3-methylbutyl]amino]-1-[4-(tert-butoxy)benzyl]-2-oxoethyl]amino)carbonyl]-5-[(tert-butoxycarbonyl)amino]pentyl]amino)-6-oxohexylcarbamate (lii)
methyl 2-(bromomethyl)-3-nitrobenzoate (li)
Reference 1:
    bringmann, g.; et al.; a short and productive synthesis of (r)-alpha-lipoic acid. z naturforsch b - j chem sci 1999, 54, 5, 655.
Reference 2:
    laban, g.; gewald, r. (asta medica ag); process for the preparation of enantiomerically pure diesters of 3-hydroxyoctandioic acid by asymmetric catalytic hydrogenation. de 19709069; ep 0863125; us 6013833 .
Reference 3:
    paust, j.; klatt, m.j.; niebel, m. (basf ag); method for producing lipoic acid and dihydrolipoic acid. wo 0210151 .

Route 7
both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (lx) were separated employing either (+)- or (-)-alpha-methylbenzylamine. esterification of the (r)-(-)-enantiomer with hcl-meoh provided the chloro hydroxy ester (lxi). further chlorination of (lxi) with socl2 and pyridine proceeded with inversion of configuration at c-6 to furnish the (s)-dichloro derivative (lxii). the cyclic disulfide (l) was then prepared by treatment of chloride (lxii) with sulfur and sodium sulfide in boiling etoh. basic hydrolysis of the methyl ester group of (lxii) then afforded (r) alpha lipoic acid. the title compound was also obtained from the (s)-(+)-acid (lxiii). reaction of hydroxy acid (lxiii) with methanesulfonyl chloride produced the chloro mesylate (lxiv), which was then cyclized to the target disulfide in the presence of sulfur and na2s.
List of intermediates No.
Reference 2:
    villani, f.; nardi, a.; salvi, a.; falabella, g.; synthesis of r(+)alpha-lipoic acid. wo 0230919 .
Reference 1:
    laban, g.; beisswenger, t.; gewald, r. (awd.pharma gmbh & co. kg); preparation and use of the pure enantiomers of 8-chloro-6-sulfonyloxy-octanoic acid and its alkyl esters and of the pure enantiomers of 6,8-dichloro-octanoic acid and its alkyl esters. de 19533881; ep 0763533; us 5731448 .
Reference 3:
    laban, g.; beisswenger, t.; gewald, r. (awd.pharma gmbh & co. kg); preparation and utilisation of pure enantiomers of 8-halogen-6-hydroxyoctanoic acid, their alkyl esters and their salts with pure enantiomers of alpha-methyl-benzylamines. de 19533882; ep 0763516; us 5869713 .

Route 8
the reaction of the chiral dibenzoyloxy-dihydropyran (lxv) with h2so4 and hgso4 gives the unsaturated aldehyde (lxvi), which is condensed with the phosphorane (lxvii) to yield the hepatdienoic ester (lxviii). the hydrogenation of (lxviii) with h2 over pd/c affords the heptanoic ester (lxix), which is treated with ts-cl and pyridine to provide the tosyloxy derivative (lxx). the cyclization of (lxx) by means of k2co3 gives the chiral epoxide (lxxi), which is condensed with vinylmagnesium bromide (lxxii) to yield 6(s)-hydroxy-8-nonenoic acid methyl ester (lxxiii). the oxidation of the terminal double bond of (lxxiii) with ozone affords the carbaldehyde (lxxiv), which is reduced with nabh4 to provide 6(s),8-dihydroxyoctanoic acid methyl ester (xlviii). the reaction of (xlviii) with ms-cl and pyridine gives the dimesylate (xlix), which is treated with na2s2 to yield the lipoic acid methyl ester (l), which is hydrolyzed to the target acid with koh in h2o.
List of intermediates No.
5-(methylsulfanyl)-6-(trifluoromethyl)indoline (lxvii)
benzhydryl (6r,7r)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (lxxii)
Reference 1:
    adger, b.; et al.; the synthesis of (r)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. bioorg med chem 1997, 5, 2, 253.
Reference 2:
    adger, b.; et al.; application of enzymatic baeyer-villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (r)-(+)-lipoic acid. j chem soc chem commun 1995, 15, 1563.
Reference 3:
    mccague, r.; roberts, s.m.; adger, b.m. (celltech group plc); process for the production of lipoic acid. wo 9638437 .
Reference 4:
    villani, f.; nardi, a.; salvi, a.; falabella, g.; synthesis of r(+)alpha-lipoic acid. wo 0230919 .

Route 9
diisopropylidene mannitol (i) was first converted into the dibutyltin derivative (ii), which was subsequently mono-benzylated to (iii). acetylation of (iii) with acetic anhydride in pyridine gave (iv). after acidic hydrolysis of the isopropylidene ketals of (iv), the resultant tetraol (v) was converted into tetramesylate (vi). reductive elimination in (vi) with zn and nai produced diene (vii). the acetate group of (vii) was then hydrolyzed to (viii) using naome. intermediate (viii) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (ix), which underwent a claisen rearrangement to the diene-ester (x). selective hydroboration-oxidation of the terminal double bond of (x) yielded the primary alcohol (xi). subsequent benzyl group hydrogenolysis in (xi) furnished the target intermediate diol (xii).
List of intermediates No.
8-nonenoic acid (i)
Reference 1:
    rao, a.v.r.; et al.; synthesis of (3r,4r)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: application to (r)-(+)-alpha-lipoic acid. tetrahedron lett 1987, 28, 19, 2183.
Reference 2:
    yadav, j.s.; et al.; synthesis of (3r,4r)-1,2-divinylglycol and its unsymmetrical derivatives: an application to the synthesis of r-(+)-alpha lipoic acid. j carbohydr chem 1990, 9, 2-3, 307.

Route 10
alkylation of the dianion of octyl acetoacetate (xiii) with 4-iodobutyronitrile (xiv) provided the cyano keto ester (xv). enantiospecific reduction of (xv) utilizing bakers yeast gave rise to the desired (s)-hydroxy ester (xvi) in high enantiomeric excess. subsequent ester group reduction in (xvi) by means of libh4 provided diol (xvii). the target dihydroxy ester (xii) was then obtained by alcoholysis of nitrile (xvii) under acidic conditions.
List of intermediates No.
Reference 1:
    jacobs, h.k.; gopalan, a.s.; stereochemical control of yeast reductions: synthesis of r-(+)-alpha-lipoic acid. tetrahedron lett 1989, 30, 42, 5705.

Route 11
in a related method, keto ester (xx) was prepared by claisen condensation of the lithium enolate of octyl acetate (xviii) with 4-chlorobutanoyl chloride (xix). reduction of the beta-keto ester (xx) with bakers yeast gave rise to the (s)-alcohol (xxi). subsequent ester group reduction in (xxi) with libh4 furnished diol (xxii), which was protected as the acetonide (xxiii) upon treatment with 2,2-dimethoxypropane under acidic conditions. displacement of the chloride of (xxiii) with the sodium salt of diethyl malonate afforded the substituted malonate (xxiv). decarbethoxylation of malonate (xxiv) to mono-ester (xxv) was accomplished employing nacn in hot dmso. the target dihydroxy ester (xii) was then obtained by acidic acetonide (xxv) hydrolysis.
List of intermediates No.
(2,4-difluorophenyl)(4-piperidinyl)methanone (xix)
Reference 1:
    jacobs, h.k.; gopalan, a.s.; bakers yeast reduction of alkyl 6-chloro-3-oxohexanoates: synthesis of (r)-(+)-alpha-lipoic acid. j chem soc - perkins trans i 1990, 7, 1897.

Route 12
esterification of diisopropylidene mannitol (i) with benzoyl chloride in pyridine afforded dibenzoate (ii). hydrolysis of the isopropylidene ketals of (ii) with aqueous hoac gave tetraol (iii), which was further converted to tetramesylate (iv) on treatment with methanesulfonyl chloride and pyridine. reductive elimination of the mesylate groups of (iv) using zn dust and nai yielded diene (v). the benzoate esters of (v) were then removed by treatment with sodium methoxide. the resultant divinylglycol (vi) was reacted with dibutyltin oxide to produce the tin derivative (vii), which was converted to the target intermediate, themono-benzyl ether (viii), by treatment with benzyl bromide in hot dmf.
List of intermediates No.
8-nonenoic acid (i)
Reference 1:
    rao, a.v.r.; et al.; synthesis of (3r,4r)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: application to (r)-(+)-alpha-lipoic acid. tetrahedron lett 1987, 28, 19, 2183.
Reference 2:
    yadav, j.s.; et al.; synthesis of (3r,4r)-1,2-divinylglycol and its unsymmetrical derivatives: an application to the synthesis of r-(+)-alpha lipoic acid. j carbohydr chem 1990, 9, 2-3, 307.

Route 13
racemic tetrahydro-2-furylmethanol (i) was converted to tosylate (ii), which was further displaced by kcn to yield nitrile (iii). basic hydrolysis of nitrile (iii), followed by fischer esterification of the resultant carboxylic acid (iv) provided ethyl ester (v). enzymatic resolution of racemic ester (v) by means of the lipase from candida cylindracea generated a mixture of the (r)-acid (vi) and the unreacted (s)-ester (vii), which were separated by column chromatography. the desired (s) ester (vii) was then reduced to alcohol (viii) with lialh4 in cold et2o. regioselective opening of the cyclic ether (viii) with iodotrimethylsilane in acetone furnished the acetonide of 6-iodo-1,3-hexanediol (ix). alkylation of benzyl methyl malonate (x) with iodide (ix) provided malonate (xi). hydrogenolysis of the benzyl ester group of (xi), followed by thermal decarboxylation led to ester (xii). the target dihydroxy ester precursor (xiii) was then obtained by acid-catalyzed hydrolysis of the acetonide function.
List of intermediates No.
Reference 1:
    laxmi, y.r.s.; iyengar, d.s.; chemoenzymatic synthesis of methyl (6s)-(-)-6,8-dihydroxyoctanoate: a precursor to (r)-(+)-alpha-lipoic acid. synthesis (stuttgart) 1996, 5, 594.

Route 14
addition of vinylmagnesium bromide to 2-nitrocyclohexanone (xiv) afforded the nitro alcohol (xv). ring cleavage of (xvi) in the presence of anhydrous cuso4 absorbed on silica gel gave the nitro ketone (xvi). nitro group hydrolysis in (xvi) by successive treatment with naome and h2so4 in meoh furnished oxo ester (xvii) as the main product. this was enantiospecifically reduced with bakers yeast to yield the (s)-alcohol (xviii). selective methyl ether cleavage with tetrabutylammonium iodide and bf3 provided the dihydroxy ester precursor (xiii).
List of intermediates No.
Reference 1:
    bezbarua, m.s.; et al.; a short enantioselective formal synthesis of methyl (s)-(-)-6,8-dihydroxyoctanoate: a key intermediate for the synthesis of r-(+)-alpha-lipoic acid. synthesis (stuttgart) 1996, 11, 1289.

Route 15
a further procedure for the preparation of the key intermediate (xiii) utilized the chiral starting material (s)-4-benzyloxy-1,2-butanediol (xix), easily accessible from (s)-malic acid. inversion of the configuration of (xix) was accomplished via formation of dimesylate (xx), followed by displacement with potassium acetate in refluxing ac2o. the resultant diacetate (xxi) was hydrolyzed to the required (r)-diol (xxii) by treatment with k2co3 in meoh. conversion of (xxii) into epoxide (xxiv) was performed through the benzylidene ketal (xxiii), following the reported procedure for the corresponding (s)-enantiomer. copper(i)-catalyzed addition of 3-butenylmagnesium bromide (xxv) to epoxide (xxiv) furnished alcohol (xxvi), which was further protected as the benzyl ether (xxvii). hydroboration of olefin (xxvii) with in situ generated disiamylborane, followed by oxidative work-up gave rise to the primary alcohol (xxviii). this was oxidized with pyridinium dichromate to the carboxylic acid (xxix), which was further esterified by means of methanolic hcl to afford ester (xxx). then, catalytic hydrogenolysis of the di(benzyloxy) ester (xxx) yielded the target intermediate dihydroxyester (xiii).
List of intermediates No.
2-cyanoethyl 4-methoxy-3-oxobutanoate (xxv)
(1r,2s,4s,6r,8s,10s,11r,12s,14r)-11-(benzyloxy)-8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,14-dimethyl-5-[(z)-phenylmethylidene]-6-[(trimethylsilyl)oxy]-15-oxatetracyclo[6.6.1.0~1,10~.0~2,6~]pentadecan-12-ol (xxiv)
Reference 1:
    brookes, m.h.; et al.; syntheses of alpha-(r)- and alpha-(s)-lipoic acid from (s)-malic acid. j chem soc - perkins trans i 1988, 1, 9.

Route 16
a further procedure utilized the (s)-keto ester (xxxi) as the chiral starting material. baeyer-villiger oxidation of cyclohexanone (xxxi) with m-cpba in the presence of a phosphate buffer at ph 8 provided two regioisomeric chiral lactones (xxxii) and (xxxiii), which were separated by column chromatography. the major isomer (xxxii) was subsequently reduced with lialh4 to furnish triol (xxxiv). the 1,3-dihydroxy moiety of (xxxiv) was then protected as the acetonide derivative (xxxv) employing 2,2-dimethoxypropane. the requisite ester (xxxvii) was prepared by stepwise oxidation of the primary alcohol (xxxv) to the aldehyde (xxxvi) using pyridinium dichromate, and then to the corresponding carboxylic acid with m-cpba, followed by esterification with ethereal diazomethane to (xxxvii). hydrolysis of the acetonide (xxxvii) by means of p-toluenesulfonic acid in methanol led to the target intermediate, the dihydroxy ester (xiii).
List of intermediates No.
Reference 1:
    ganaha, m.; et al.; synthesis of methyl (s)-(-)-6,8-dihydroxyoctanoate as a precursor of (r)-(+)-alpha-lipoic acid. biosci biotechnol biochem 1999, 63, 11, 2025.

Route 17
the olefinic diester (xxxviii) was subjected to oso4-catalyzed asymmetric dihydroxylation using hydroquinidine 1,4-phthalazinediyl diether [(dhqd)2-phal] as chiral ligand to afford diol (xxxix). this was converted to the cyclic sulfate (xl) by treatment with socl2, followed by rucl3-catalyzed naio4 oxidation of the intermediate sulfite. regioselective reduction of sulfate (xl) at the alpha position with nabh4 in dma led to the (3s)-alcohol (xli). further selective reduction of the ethyl ester group of (xli) was achieved by treatment with nabh4-et3n in meoh-dmf, yielding the target intermediate dihydroxy ester (xiii).
List of intermediates No.
Reference 1:
    upadhya, t.t.; et al.; asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of r-(+)-alpha-lipoic acid. tetrahedron lett 2001, 42, 29, 4891.

Route 18
the key dihydroxy ester intermediate (xiii) was also obtained by asymmetric hydrogenation of hydroxy ketoester (xliii) in the presence of (s)-binap-dichlororuthenium catalyst. the precursor hydroxy ketoester (xliii) was prepared by two alternative procedures. in one method, the racemic dihydroxy ester (xlii) was selectively oxidized to (xliii) by means of naocl. in another method, the unsaturated keto ester (xliv) was epoxidized by means of sodium percarbonate, and the resultant epoxide (xlv) was then reduced to the hydroxy ketoester (xliii) by catalytic hydrogenation over pto2.
List of intermediates No.
Reference 1:
    gewald, r. (asta medica ag); method for producing enantiomer-free 6,8-dihydroxyoctanoic acid esters by means of asymmetric, catalytic hydrogenation. de 10036516; wo 0210113 .

Route 19
the intermediate 6(s)-hydroxy-8-nonenoic acid methyl ester (iii) has been obtained by enantioselective allylation of 6-oxohexanoic acid methyl ester (i) with allyltributylstannane (ii) catalyzed by the chiral catalyst (r)-binol/ti(o-ipr)4 in refluxing dichloromethane (other binol/metal catalysts have also been studied).
List of intermediates No.
ethyl 4-(diethoxyphosphoryl)-1-[4-(2-ethoxy-2-oxoethyl)-1-oxo-2,3-dihydro-1h-inden-2-yl]-1h-imidazole-2-carboxylate (ii)
Reference 1:
    zimmer, r.; et al.; enantioselective synthesis of (s)- and (r)-6-hydroxy-8-nonene-carboxylates by asymmetric catalysis: a formal synthesis of (r)-alpha-lipoic acid and its (s)-antipode. tetrahedron asymmetry 2000, 11, 4, 879.

Route 20
1,6-hexanediol (i) was protected as the mono-tetrahydropyranyl ether (ii), and the free hydroxyl group was subsequently oxidized to aldehyde (iii) under swern conditions. reformatskii reaction of aldehyde (iii) with the organozinc reagent generated from ethyl bromoacetate yielded the racemic hydroxy ester (iv). the requisite (s)-enantiomer (vi) was obtained via oxidation of (iv) to oxo ester (v) using pyridinium chlorochromate, and then asymmetric hydrogenation in the presence of (s)-(-)-2,2-bis(diphenylphosphino)-1,1-binaphthyl dichlororuthenium complex. oxo ester (v) was also prepared by sncl2-catalyzed insertion of ethyl diazoacetate into aldehyde (iii). the chiral hydroxy ester (vi) was then reduced to diol (vii) by means of nabh4-cuso4. after conversion of (vii) to the corresponding dimesylate (viii), removal of the tetrahydropyranyl protecting group under acidic conditions gave alcohol (ix). this was sequentially oxidized with pcc to aldehyde, and then with ag2o to furnish the target dimesylate acid intermediate (x).
List of intermediates No.
Reference 1:
    upadhya, t.t.; et al.; asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of r-(+)-alpha-lipoic acid. tetrahedron lett 2001, 42, 29, 4891.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名R-(+)-硫辛酸;英文名d-Thioctic acid;(R)-(+)-alpha-Lipoic acid;(R)-(+)-Thioctic acid;Dexlipotam;CAS[1200-22-2]

 
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